scholarly journals Plasma and Intracellular Population Pharmacokinetic Analysis of Tenofovir in HIV-1-Infected Patients

2011 ◽  
Vol 55 (11) ◽  
pp. 5294-5299 ◽  
Author(s):  
Gautam Baheti ◽  
Jennifer J. Kiser ◽  
Peter L. Havens ◽  
Courtney V. Fletcher
Keyword(s):  
Rate Constant ◽  
Sequential Analysis ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Distribution Volume ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Response Model ◽  
Indirect Response Model ◽  
Indirect Response

ABSTRACTThe relationships among the dose of tenofovir disoproxil fumarate (TDF), tenofovir (TFV) plasma concentrations, and intracellular TFV diphosphate (TFV-DP) concentrations are poorly understood. Our objective was to characterize TFV and TFV-DP relationships. Data were pooled from two studies in HIV-infected persons (n= 55) on stable antiretroviral therapy. TFV and TFV-DP were measured with validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods. Nonlinear mixed effects modeling (NONMEM 7) was used to develop the population model and explore the influence of covariates on TFV. A sequential analysis approach was utilized. A two-compartment model with first-order absorption best described TFV PK (FOCEI). An indirect stimulation of response model best described TFV-DP, where formation of TFV-DP was driven by plasma TFV concentration. Final plasma population estimates were as follows: absorption rate constant, 1.03 h−1; apparent clearance (CL/F), 42 liters/h (33.5% interindividual variability [IIV]); intercompartment clearance, 181 liters/h; apparent central distribution volume (Vc/F), 273 liters (64.8% IIV); and apparent peripheral distribution volume (Vp/F), 440 liters (46.5% IIV). Creatinine clearance was the most significant covariate on CL/F and Vc/F. The correlation between CL/F and Vc/F was 0.553. The indirect response model for TFV-DP resulted in estimates of the maximal intracellular concentration (Emax), the TFV concentration producing 50% ofEmax(EC50), and the intracellular elimination rate constant (kout) of 300 fmol/106cells (82% IIV), 100 ng/ml (106% IIV), and 0.008 h−1, respectively. The estimatedkoutgave an 87-h TFV-DP half-life. A predictive check assessment indicated satisfactory model performance. This model links formation of TFV-DP with plasma TFV concentrations and should facilitate more informed investigations of TFV clinical pharmacology.

Pharmacokinetic-Pharmacodynamic Modeling of the Respiratory Depressant Effect of Alfentanil 

1999 ◽  
Vol 91 (1) ◽  
pp. 144-155 ◽  
Author(s):  
Thomas Bouillon ◽  
Christina Schmidt ◽  
Gudrun Garstka ◽  
Dirk Heimbach ◽  
Dieter Stafforst ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Respiratory Depression ◽  
Pharmacodynamic Modeling ◽  
Model Parameters ◽  
Pharmacokinetic Data ◽  
Indirect Response Models ◽  
Response Model ◽  
Indirect Response Model ◽  
Indirect Response ◽  
Arterial Blood

Background Although respiratory depression is the most well-known and dangerous side effect of opioids, no pharmacokinetic-pharmacodynamic model exists for its quantitative analysis. The development of such a model was the aim of this study. Methods After institutional approval approval and informed consent were obtained, 14 men (American Society of Anesthesiologists physical status I or II; median age, 42 yr [range, 20-71 yr]; median weight, 82.5 kg [range, 68-108 kg]) were studied before they underwent major urologic surgery. An intravenous infusion of alfentanil (2.3 microg x kg(-1) x min(-1)) was started while the patients were breathing oxygen-enriched air (fraction of inspired oxygen [FIO2 = 0.5) over a tightly fitting continuous positive airway pressure mask. The infusion was discontinued when a cumulative dose of 70 microg/kg had been administered, the end-expiratory partial pressure of carbon dioxide (PE(CO2) exceeded 65 mmHg, or apneic periods lasting more than 60 s occurred During and after the infusion, frequent arterial blood samples were drawn and analyzed for the concentration of alfentanil and the arterial carbon dioxide pressure (PaCO2). A mamillary two-compartment model was fitted to the pharmacokinetic data. The PaCO2 data were described by an indirect response model The model accounted for the respiratory stimulation resulting from increasing PaCO2. The model parameters were estimated using NONMEM. Simulations were performed to define the respiratory response at steady state to different alfentanil concentrations. Results The indirect response model adequately described the time course of the PaCO2. The following pharmacodynamic parameters were estimated (population means and interindividual variability): EC50, 60.3 microg/l (32%); the elimination rate constant of carbon dioxide (Kel), 0.088 min(-1) (44%); and the gain in the carbon dioxide response, 4(28%) (fixed according to literature values). Simulations revealed the pronounced role of PaCO2 in maintaining alveolar ventilation in the presence of opioid. Conclusions The model described the data for the entire opioid-PaCo2 response surface examined. Indirect response models appear to be a promising tool for the quantitative evaluation of drug-induced respiratory depression.

scholarly journals An indirect response model of homocysteine suppression by betaine: optimising the dosage regimen of betaine in homocystinuria

2002 ◽  
Vol 54 (2) ◽  
pp. 140-146 ◽  
Author(s):  
Angela Matthews ◽  
Trevor N. Johnson ◽  
Amin Rostami-Hodjegan ◽  
Anupam Chakrapani ◽  
J. Edward Wraith ◽  
...  
Keyword(s):  
Dosage Regimen ◽  
Response Model ◽  
Indirect Response Model ◽  
Indirect Response

Mixed-effects Modeling of the Intrinsic Ventilatory Depressant Potency of Propofol in the Non-steady State

2004 ◽  
Vol 100 (2) ◽  
pp. 240-250 ◽  
Author(s):  
Thomas Bouillon ◽  
Joergen Bruhn ◽  
Lucian Radu-Radulescu ◽  
Corina Andresen ◽  
Carol Cohane ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Steady State ◽  
Time Course ◽  
Minute Ventilation ◽  
Carbon Dioxide Production ◽  
Response Model ◽  
Indirect Response Model ◽  
Indirect Response ◽  
Arterial Blood ◽  
Ventilatory Depression

Background Despite the ubiquitous use of propofol for anesthesia and conscious sedation and numerous publications about its effect, a pharmacodynamic model for propofol-induced ventilatory depression in the non-steady state has not been described. To investigate propofol-induced ventilatory depression in the clinically important range (at and below the metabolic hyperbola while carbon dioxide is accumulating because of drug-induced ventilatory depression), the authors applied indirect effect modeling to Paco2 data at a fraction of inspired carbon dioxide of 0 during and after administration of propofol. Methods Ten volunteers underwent determination of their carbon dioxide responsiveness by a rebreathing design. The parameters of a power function were fitted to the end-expiratory carbon dioxide and minute ventilation data. The volunteers then received propofol in a stepwise ascending pattern with use of a target-controlled infusion pump until significant ventilatory depression occurred (end-tidal pressure of carbon dioxide > 65 mmHg and/or imminent apnea). Thereafter, the concentration was reduced to 1 microg/ml. Propofol pharmacokinetics and the Paco2 were determined from frequent arterial blood samples. An indirect response model with Bayesian estimates of the pharmacokinetics and carbon dioxide responsiveness in the absence of drug was used to describe the Paco2 time course. Because propofol reduces oxygen requirements and carbon dioxide production, a correction factor for propofol-induced decreasing of carbon dioxide production was included. Results The following pharmacodynamic parameters were found to describe the time course of hypercapnia after administration of propofol (population mean and interindividual variability expressed as coefficients of variation): F (gain of the carbon dioxide response), 4.37 +/- 36.7%; ke0, CO2, 0.95 min-1 +/- 59.8%; baseline Paco2, 40.9 mmHg +/- 12.8%; baseline minute ventilation, 6.45 l/min +/- 36.3%; kel, CO2, 0.11 min-1 +/- 34.2%; C50,propofol, 1.33 microg/ml +/- 49.6%; gamma, 1.68 +/- 21.3%. Conclusion Propofol at common clinical concentrations is a potent ventilatory depressant. An indirect response model accurately described the magnitude and time course of propofol-induced ventilatory depression. The indirect response model can be used to optimize propofol administration to reduce the risk of significant ventilatory depression.

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